The present invention relates to new heparinic derivatives having a modified structure, obtained by treating commercial or purified or low molecular weight heparins in a basic medium, optionally in the presence of a salt and of a reducing agent.
These new heparinic derivatives can also be obtained by heating the heparinic derivatives described in the Italian patent application No. 3504 A/88 filed on June 10, 1988, in a neutral or basic medium, optionally in the presence of a salt or of a reducing agent. The new heparin derivatives possess chemical-physical properties different both from those of the commercial heparins and from those of the heparinic derivatives described in the Italian patent application No. 3504 A/88 and moreover they show biological activities different from those of both the classes of products above mentioned. In particular, the new derivatives do not hold the anticoagulant activities typical of the heparinic structures, while they keep unchanged or even enhanced peculiar biological activities like, for instance, the anticalculous activity, which makes them suitable as drugs for the cure and the prevention of the nephrolithiases. Bowyer R. G. et al, Clin. Chim. Acta, 95, 23, (1979) demonstrated that the heparin is a strong inhibitor of the formation and of the aggregation of the crystals of calcium oxalate, while Baggio B., Int. Meeting on: "Inhibitors of crystallization in renal lithiasis and their clinical application" Bologna, Sept. 7-9, (1987), showed that heparin lowers the urinary excretion of the oxalate. The heparin is therefore a potential drug against the calculosis, but, due to its specific anticoagulant and antithrombotic activities, it cannot be used in the nephrolithiases in general and in those calcium-oxalic acid conditions in particular. The new products described in the present invention, on the contrary, can be used in the treatment of nephrolithiases, which are chronic diseases that require prolonged treatments with highly specific drugs devoid of side effects, because they do not more possess the anticoagulant properties typical of heparin.
The heparinic derivatives object of the present invention possess chemical-physical properties totally different from those of the products described by Mardiguian J. S. in the European patent publication EP0133078 and by Hirano S. et al. in Conn. Tissue Res, 3, 73-79, (1975) as shown by the average molecular weight which remains substantially unchanged, so proving the lack of depolymerization, and by the lack of absorption at 225-230 nm in U.V. and of peaks corresponding to the resonances of the double bond in the .sup.13 C-NMR spectrum, indexes of the lack of the double bond in the positions 4 and 5 of the uronic acid. Moreover they do not even show the chemical-physical properties of the compounds isolated by Sampson P. and Meyer K. in Proc. Nat. Acad. Sci. U.S.A. 68, 2329-31, (1971) as the .sup.13 C-NMR spectrum of the compounds obtained in the present invention shows unchanged the position and the intensity of the signal of the carbon atom in position 6 of the glucosamine and shows unchanged the intensity ratio between the 6-sulfated carbon atom and the 6-desulfated carbon atom that should change in case of formation of 3,6-anhydroglucosamine because of the participation of the 6-sulfated carbon atom in the formation of the anhydroderivative. Lastly, the products object of the present invention differ in the chemical-physical properties from those claimed in the Italian patent application No. 3504 A/88 as shown, for instance, by the lack of the peaks at about 53 and 54 p.p.m. in the .sup.13 C-NMR spectrum.